title: Mice lacking the p43 mitochondrial T3 receptor become glucose intolerant and insulin resistant during aging.
abstract: Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43-/- mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43-/- mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43-/- mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.
authors.affiliation: INRA, Institut National de la Recherche Agronomique, UMR866 Dynamique Musculaire et Métabolisme, Montpellier, France; Université Montpellier 1, Montpellier, France; Université Montpellier 2, Montpellier, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Bertrand
authors.forename: Emilie
authors.initials: E
authors.lastname: Blanchet
authors.forename: Laurence
authors.initials: L
authors.lastname: Pessemesse
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Annicotte
authors.forename: Christine
authors.initials: C
authors.lastname: Feillet-Coudray
authors.forename: Béatrice
authors.initials: B
authors.lastname: Chabi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levin
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.forename: Gérard
authors.initials: G
authors.lastname: Cabello
authors.forename: Chantal
authors.initials: C
authors.lastname: Wrutniak-Cabello
authors.forename: François
authors.initials: F
authors.lastname: Casas
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D002245:Carbon Dioxide / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency*; D010101:Oxygen Consumption / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000172:deficiency*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D024101:Mitochondrial Proteins; D011988:Receptors, Thyroid Hormone; D002245:Carbon Dioxide